This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both.
Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist. PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N.Y Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996). PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991). PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
Jones, et al, (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline 1. 
Jones, et al, described the enol ether 2 (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound 3 (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J. Med. Chem., 41, 291, 1998). 
Zhi, et al, described the ether 7 as a PR antagonist (J. Med. Chem., 41, 291, 1998). 
Combs, et al., disclosed the amide 8 as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 
Perlman, et. al., described the vitamin D analog 9 as a PR higand (Tet. Letters, 35, 2295, 1994). 
Hamann, et al, described the PR antagonist 10 (Ann. N.Y. Acad. Sci., 761, 383, 95). 
Chen, et al, described the PR antagonist 11 (Chen, et al, POI-37, 16th Int. Cong. Het. Chem, Montana, 1997). 
Kurihari, et. al., described the PR ligand 12 (J. Antibiotics, 50, 360, 1997). 
A number of publications reported the synthesis and utilities of benzodiazinones and benzoxazines. Included in this literature is the patent by Kubla et al. (U.S. Pat. No. 4,666,913) which claimed that the compound such as A and B could be used as cardiotonic agents. Ning et al. reported the synthesis of quinazolinones such as C.
Gromachevskaya et al. (Chem. Heterocycl. Compd. (N.Y.), 33(10), 1209-1214 (1998)) studied the bromination process of certain benzoxazines such as compound D. Kobzina et al. (U.S. Pat. No. 3,917,592) claimed that compounds such as E can be used as a herbicidal agent. 
Pflegel et al. (Pharmazie, 37(10), 714-717(1982)) disclosed quinazolin-2-thiones such as compound F in their study of polarography of heterocyclics. No activity of the compound F was mentioned. 
U.S. Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2-4 days to prevent breakthrough bleeding.
This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents. This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestins and progestins, an estrogen, such as ethinyl estradiol.
These regimens and combinations may be administered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake. The uses herein for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding.
The use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combination with an estrogen or progestin or both. These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins.
The progestins of these combinations may be administered alone or in combination with an estrogen for the first 14-24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 xcexcg to about 150 xcexcg levonorgestrel per day, preferably equal in activity to from about 35 xcexcg to about 100 xcexcg levonorgestrel per day. An antiprogestin may then be administered alone or in combination with an estrogen for a period of 1 to 11 days to begin on any cycle day between day 14 and 24. The anti-progestin in these combinations may be administered at a dose of from about 2 xcexcg to about 50 xcexcg per day and the estrogen may be administered at a dose of from about 10 xcexcg to about 35 xcexcg per day. In an oral administration, a package or kit containing 28 tablets will include a placebo tablet on those days when the antiprogestin or progestin or estrogen is not administered.
In a preferred embodiment of this invention, the progestins of this invention may be administered alone or in combination with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or in combination with an estrogen, for from 1 to 7 days.
The estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol.
Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestiimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestirate . Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone.
Examples of orally administered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg of levonorgestrel. An antiprogestin compound of this invention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28. It is most preferred that the daily dosages of each relevant active ingredient be incorporated into a combined, single daily dosage unit, totaling 28 daily units per 28-day cycle.
In another regimen, a progestational agent may be coadministered for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, with an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 xcexcg. This may be followed as described above with an antiprogestin administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28.
Still another regimen within the scope of this invention will include coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, being administered at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg levonorgestrel, and an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 xcexcg. This will be followed on days 22 to 24 by coadministration of an antiprogestin (2 to 50 mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose of from about 10 to about 35 xcexcg. From day 25 to day 28, this regimen may be followed by no administration or administration of a placebo.
This invention also kits or packages of pharmaceutical formulations designed for use in the regimens described herein. These kits are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle. Preferably each kit will include oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combined daily dosages indicated.
According to the regimens described above, one 28-day kit may comprise.
a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of from 1 to 11 daily dosage units of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered.
A preferred embodiment of this kit may comprise:
a) an initial phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
Another 28-day cycle packaging regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of from 1 to 7 daily dosage units of an antiprogestin of this invention at a daily dose of from about 2 to 50 mg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the kit described above may comprise:
a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin administered at a daily dose of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
A further 28-day packaged regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg,
b) a second phase of from 1 to 7 daily dose units, each daily dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the package or kit just described comprises:
a) a first phase of 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg;
b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
In each of the regimens and kits just described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered. It is also understood that the daily dose units described are to be administered in the order described, with the first phase followed in order by the second and third phases. To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle. It is further preferred that each package or kit comprise a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package or dial dispenser packages known in the art.
In this disclosure, the terms anti-progestational agents, anti-progestins and progesterone receptor antagonists are understood to be synonymous. Similarly, progestins, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity.
These dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation. In the descriptions herein, reference to a daily dosage unit may also include divided units which are administered over the course of each day of the cycle contemplated.
Compounds of this invention which may be used as the anti-progestational agents in the kits, methods and regimens herein are those of the Formula I: 
wherein:
R1, R2 are independent substituents selected from the group which includes H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA;
or R1 and R2 are fused to form:
a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring;
b) an optionally substituted 3 to 8 membered spirocyclic alkenyl; or
c) an optionally substituted 3 to 8 membered heterocyclic ring containing one to three heteroatoms from the group including O, S and N; the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 thioalkyl, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, NH2, xe2x80x94NH(C1 to C6 alkyl), or xe2x80x94N(C1 to C6 alkyl)2;
RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl,
RB is H, C1 to C3 alkyl, substituted C1 to C3 alkyl,
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, or substituted alkynyl, CORC,
RC is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl,
R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, alkynyl, or substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, substituted C1 to C6 aminoalkyl,
R5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below, 
X is taken from the group including halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, alkynyl, or substituted alkynyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CORD, OCORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, substituted C1 to C3 alkyl;
Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, amino, aminoalkyl, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; or
R5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, NO2, amino, and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORF, or NRGCORF;
RF is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RG is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R6 is H or C1 to C3 alkyl;
G1 is O, NR7, or CR7R8;
G2 is CO or CR7R8;
provided that when G1 is O, G2 is CR7R8, and G1 and G2 cannot both be CR7R8;
R7 and R8 are independent substituents selected from H or an optionally substituted alkyl, aryl, or heterocyclic moiety;
or pharmaceutically acceptable salt thereof
Preferred antiprogestin compounds of this invention include those of Formula I: 
wherein:
R1 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA;
R2 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA; or
R1 and R2 are fused to form an optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring containing one to three heteroatoms from the group including O, S and N, as described above;
RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl,
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, or substituted alkynyl, CORC;
RC is H, C1 to C4 alkyl, substituted C1 to C4 alkyl, aryl, substituted aryl, C1 to C4 alkoxy, substituted C1 to C4 alkoxy, C1 to C4 aminoalkyl, or substituted C1 to C4 aminoalkyl;
R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, substituted C1 to C6 aminoalkyl,
R5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
X is selected from halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, CORD, OCORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; or
R5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, NO2 amino, and C1 to C3 alkyl, C1 to C3 alkoxy;
R6 is H, or C1 to C3 alkyl.
G1 is O, NR7, or CR7R8 
G2 is CO or CR7R8, with the proviso that when G1 is O, G2 is CR7R8, and G1 and G2 cannot both be CR7R8;
wherein R7 and R8 are independent substituent selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, or substituted heterocyclic
or a pharmaceutically acceptable salt thereof.
Still, more preferred antiprogestin compounds include those of the formula: 
wherein:
R1=R2 and are selected from C1 to C3 alkyl, substituted C1 to C3 alkyl, or spirocyclic alkyl constructed by fusing R1 and R2 to form a 3 to 6 membered spirocyclic ring;
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, xe2x80x94COH, xe2x80x94CO(C1 to C4 alkyl) or xe2x80x94CO(C1 to C4 alkoxy);
R4 is H, halogen, NO2, C1 to C3 alkyl, substituted C1 to C3 alkyl,
R5 is a disubstituted benzene ring containing the substituents X, and Y as shown below 
X is taken from the group including halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, C1 to C3 thioalkoxy,
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, C1 to C3 thioalkoxy or
R5 is a five membered ring with the structure shown below 
U is O, S, or NR6,
R6 is H, or C1 to C3 alkyl, C1 to C4 CO2alkyl,
Xxe2x80x2 is from the group including halogen, CN, NO2, C1 to C3 alkyl and C1 to C3 alkoxy
Yxe2x80x2 is from the group including H and C1 to C4 alkyl or
R5 is a six membered ring with the structure shown 
X1 is N or CX2,
X2 is halogen, CN, alkoxy, or NO2,
G1 is O, NR7, or CR7R8 
G2 is CO or CR7R8 
provided that when G1 is O, G2 is CR7R8, and G1 and G2 cannot both be CR7R8;
wherein R7 and R8 are independent substituents selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, or substituted heterocyclic;
or pharmaceutically acceptable salt thereof.
Still, other preferred antiprogestin compounds are those of Formula I 
wherein:
R1=R2 and are selected from the group which includes CH3 and spirocyclic alkyl constructed by fusing R1 and R2 to form a 6 membered spirocyclic ring,
R3 is H, OH, NH2, CH3, substituted methyl, CORC,
RC is H, C1 to C3 alkyl, C1 to C4 alkoxy,
R4 is H, halogen, C1 to C3 alkyl,
R5 is a disubstituted benzene ring containing the substituents X, and Y as shown below 
X is taken from the group including halogen, CN, methoxy, NO2, 2-thiazole,
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H and F, or
R5 is a five membered ring with the structure shown below 
U is O, S, or NH,
Xxe2x80x2 is from the group including halogen, CN, NO2,
Yxe2x80x2 is from the group including H and C1 to C4 alkyl
G1 is O, NR7, or CR7R8 
G2 is CO or CR7R8 
provided that when G1 is O, G2 is CR7R8, and G1 and G2 cannot both be CR7R8;
R7 and R8 are independent substituent selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, or substituted heterocyclic;
and pharmaceutically acceptable salts thereof.
The antiprogestin compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof It will be understood by one skilled in the art that the number of substituents listed for spirocyclic or heterospirocyclic rings formed by fusing R1 and R2 will be determined by the size of the spirocyclic ring.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to eight carbon atoms; xe2x80x9calkenylxe2x80x9d is intended to include both straight- and branched-chain alkyl groups with at least one carbonxe2x80x94carbon double bond and two to eight carbon atoms; xe2x80x9calkynylxe2x80x9d group is intended to cover both straight- and branched-chain alkyl groups with at least one carbonxe2x80x94carbon triple bond and two to eight carbon atoms.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic just defined having one to four substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term xe2x80x9calkoxyxe2x80x9d refers to the OR group, where R is alkyl or substituted alkyl. The term xe2x80x9caryloxyxe2x80x9d is used herein to indicate the OR group, where R is aryl or substituted aryl. The term xe2x80x9calkylcarbonylxe2x80x9d refers to the RCO group, where R is alkyl or substituted alkyl. The term xe2x80x9calkylcarboxyxe2x80x9d refers to the COOR group, where R is alkyl or substituted alkyl. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing one to eight carbon atoms, which may be either same or different and the point of attachment is on the nitrogen atom The term xe2x80x9chalogenxe2x80x9d refers to Cl, Br, F, and I element.
The antiprogestin compounds of this invention can be prepared following the Schemes illustrated below: 
As demonstrated in Scheme I, the anti-progestational compounds of this invention are generally prepared by employing the suitable coupling reaction as a key step. An appropriately substituted ortho-amino benzoic acid or its derivatives such as ethyl ester (X=Br, I, Cl, or a latent coupling precursor such as alkoxy group which can be converted into OTf group suitable in the coupling reaction.) was treated with a suitable organo metallic reagent, e.g. Grignard reagent, in appropriate nonprotic solvents which include but not limited to THF or ether to give ortho-amino carbinol 2 under an inert atmosphere such as argon or nitrogen at xe2x88x9278xc2x0 C. to room temperature. The arylation of amino carbinol 2 to yield 3 can be effected by various coupling reactions including Suzuki, Stille reactions. These reactions are commonly performed in the presence of a transition metallic catalyst, e.g., palladium or nickel complex often with phosphino ligands, e.g., Ph3P, dppf, dppe or a catalyst such as palladium acetate. Under this catalytic condition, an appropriately substituted nucleophilic reagent, e.g., aryl boronic acid, arylstannane, or aryl zinc compound, is coupled with amino carbinol 2 to give 3. If a base is needed in the reaction, the commonly used bases include but not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, cesium fluoride, or potassium acetate. The most commonly used solvents in these reactions include benzene, DMF, isopropanol, ethanol, DME, ether, acetone, or a mixture of above solvent and water. The coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95xc2x0 C. The compounds of this invention 4 can be effected by treatment of amino carbinol 3 with an appropriate ketone in the presence of an suitable acid catalyst such as p-toluenesulfonic acid in a suitable solvent such as toluene, benzene under an inert atmosphere such as argon or nitrogen at room temperature to reflux.
Scheme II describes the procedure to prepare benzoxazines bearing two different substituents at position-4. The Weinreb amide 6 can be prepared from an appropriately substituted isatoic anhydride 5 when treated with N-, O-dimethylhydroxyl-amine hydrochloride salt in a protic solvent such as ethanol, or isopropanol at reflux under an inert atmosphere such as argon or nitrogen. Coupling of amide 6 with an aryl electrophile such as aryl boronic acid or arylstannane to give 7 can be effected by employing a typical coupling reaction such as Suzuki, Stille coupling procedure in a similar fashion as described for the preparation of compound 3. Treatment of Weinreb amide 7 with organo metallic compounds, e.g., alkyllithium, alkynyllithium, aryllithium, or their Grignard counterpart in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at xe2x88x9278xc2x0 to room temperature affords amino ketone 8. Conversion of ketone 8 to carbinol 9 can be effected by treatment of 8 with an organo metallic reagent such as alkyl, alkynyl, or aryl Grignard reagent in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at xe2x88x9278xc2x0 C. to room temperature. Conversion of ketone 8 to carbinol 9 can also be effected by reduction of ketone group of 8 to the carbinol moiety of 9 using an appropriate reducing reagent such as lithium aluminum hydride, sodium borohydride in a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere in the temperature ranging from 0xc2x0 C. to the boiling point of the solvent. Further conversion of 9 to the compounds of this invention can be effected as described in scheme I for the preparation of compound 4. 
Alternatively, ortho-amino ketone 8 can be prepared by treatment of ortho-amino benzonitrile 11 with an organo metallic compound such as organo lithium reagent or Grignard reagent in a suitable solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature as illustrated in Scheme 111. Benzonitrile 11 can be readily prepared from an appropriately substituted benzonitrile such as bromobenzonitrile 10 using a suitable coupling reaction such as Stille or Suzuki protocol carried out in a similar fashion as described for the preparation of the Weinreb amide 7. 
Scheme IV illustrates the synthesis of 3,4-dihydroquinazolin-2-ones. The substituted 2-aminobenzonitrile 11 is treated with an organo metallic compound such as organo lithium or Grignard reagent in a nonprotic solvent such as THF or ether under an inert atmosphere such argon or nitrogen at xe2x88x9278xc2x0 C. to room temperature to produce an imino intermediate which is reacted with a suitable carbonate such as diethyl carbonate or dimethyl carbonate in situ at 0xc2x0 C. to 60xc2x0 C. to give quinazolin-2-ones 12. Protection of quinazolin-2-ones 12 with a suitable protective group such as para-methoxybenzyl moiety can be effected by treating 12 with a suitable base such as potassium hydride, potassium t-butoxide, or sodium hydride followed by addition of a protective reagent such as para-methoxybenzyl chloride in an appropriate solvent such as DMF, or a mixture of solvents such as THF and DMF under an inert atmosphere such as nitrogen or argon at 0xc2x0 C. to room temperature. The Michael addition of a suitable organo metallic compound such as organo lithium or Grignard reagent to the protected quinazohin-2-ones 12 to give 13 can be accomplished in the presence of a suitable Lewis acid such as magnesium triflate in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at 0xc2x0 C. to room temperature. 
Removal of protective group can be effected by treating 13 with a suitable deprotecting reagent, e.g. for the para-methoxybenzyl protective group it can be removed by treatment of 13 with protic acid such as TFA or with Ceric ammonium nitrate in a suitable solvent such as methylene chloride at 0xc2x0 C. to room temperature under an inert atmosphere such as argon or nitrogen. Prior to the removal of protective group, the alkylation of 3-nitrogen can be achieved by treating 13 with an appropriate base such as sodium hydride, potassium hydride, or potassium t-butoxide in a suitable solvent such as DMF followed by quenching the reaction solution with an organo iodide or an organo triflate such as iodomethane under an inert atmosphere such as argon or nitrogen at 0xc2x0 C. to room temperature. The compounds of the present invention 14 can be accomplished when the protective group is removed with a suitable reagent, e.g. for the para-methoxybenzyl protective group it can be removed by treatment of 13 with protic acid such as TFA or with Ceric ammonium nitrate in a suitable solvent such as methylene chloride at 0xc2x0 C. to room temperature under an inert atmosphere such as argon or nitrogen.
The conversion of compounds 14 to 3,4-dihydroquinazolin-2-thiones 15 can be accomplished by treatment of 14 with a suitable sulfur reagent such as Lawesson""s reagent in a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an inert atmosphere such as argon or nitrogen at reflux.
As illustrated in scheme V, the compounds 14 or 15 can be further derivatized at position-1 via numerous approaches leading to a variety of the novel derivatives including 1-alkyl, substituted 1-alkyl, 1-carbonyl, substituted 1-carbonyl, 1-carboxy, substituted 1-carboxy derivatives. For examples, alkyl or substituted alkyl derivatives 16 or 17 can be effected by treatment of carbamate 14 or 15 with a suitable base such as sodium hydride in a suitable solvent such as DMF under an inert atmosphere such as argon or nitrogen followed by addition of an appropriate electrophile such as alkyl or substituted alkyl bromide, iodide, or triflate. Such transformation of 14 or 15 to 16 or 17 at position-1 can also be effected using biphasic condition as indicated in scheme V in which alkylation is executed using a biphasic catalyst such as tributylammonium bromide in a suitable solvent such as acetonitrile. A further example of such modification in position-i includes but not limited to the one depicted in scheme V in that heating of 14 or 15 with triethyl orthoformate affords I-substituted derivatives of compound 14 or 15. 
The acylation or carboxylation of the compound 14 or 15 at position-1 to give compound 18 or 19 can be readily effected by treatment of 14 or 15 with a suitable acylating or carboxylating reagent such as di-t-butyl dicarbonate in the presence of a suitable basic catalyst such as DMAP in a suitable solvent such as acetonitrile under an inert atmosphere such as argon or nitrogen. The amination of position-1 of compound 14 or 15 to give compounds 20 and 21 can be furnished using a suitable aminating reagent such as chloroamine in the presence of a suitable base such as sodium hydride in a suitable solvent such as THF or diethyl ether following the literature procedure (Metlesics et al. J. Org. Chem. 30, 1311(1965)).
According to scheme VI an appropriate aniline such as 4-bromoaniline 22, is reacted in the presence of a base in a suitable nonprotic solvent with an acryloyl chloride 23 to form the amide 24. The base is preferably a strong base such as sodium hydride or sodium or potassium hexamethyldisilylamide, utilizing THF as the solvent under an inert atmosphere (nitrogen or argon) from 0xc2x0 C. up to the reflux temperature of the solvent. 
Reaction of the amide 24 under strongly acidic conditions, sulfuric acid, borontrifluoride etherate, or preferably aluminum chloride either as a melt, or in an inert solvent (dichlorobenzenes) under an inert atmosphere (nitrogen or argon) from 0xc2x0 C. up to the reflux temperature of the solvent then provides the cyclic amide 25. Subsequent reaction of compound 25 with an aryl or heteroaryl boronic acid, boronic acid anhydride or trialkyl stannane then provides access to the desired biaryl compound 26. The reaction can be carried out in a solvent such as acetone, ethanol, benzene, toluene or THF, under an inert atmosphere (nitrogen or argon) from 0xc2x0 C. up to the reflux temperature of the solvent, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluoride or potassium phosphate.
The conversion of compounds 26 to thioamide 27 can be accomplished by treatment of 26 with a suitable sulfur reagent such as Lawesson""s reagent in a nonprotic solvent. such as o-xylene, chlorobenzene, or toluene under an inert atmosphere such as argon or nitrogen at reflux. 
According to scheme VII, an appropriate cyclic amide such as 25, is allowed to react with NaH in THF to form the anion species and then a benzyl halide is added to convert the starting material to the N-protected amide product, 28. Reaction of 28 with an aryl boronic acid in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium acetate permits a coupling of the two aromatic species to yield 29. The reaction is normally carried out under biphasic conditions. That is, water is often employed along with an appropriate organic solvent, such as toluene or DMF. The palladium catalyst is typically added last and the reaction mixture is refluxed in the presence of an inert gas such as nitrogen. The product is treated with a Grignard Reagent, an alkyl magnesium halide, in THF followed by the addition of ammonium chloride solution to afford the enamine derivative 30. The reduction of the double bond in 30 and removal of the protecting group can be accomplished in a single step by catalytic reduction in a Parr Hydrogenation Apparatus using palladium on charcoal to form the target compound 31. 
3-Fluoro-5-(2,4,4-trimethyl-1,2,3,4-hydro-qinolinyl)-benzonitrile (compound 35) can be prepared by Scheme VIII, a process sinmilar to Scheme VII. According to scheme VIII, compound 28 is allowed to react with a Grignard reagent, an alkyl magnesium halide, in THF followed by the addition of ammonium chloride solution to afford the enamine derivative 32. Reduction of the double bond with sodium cyanoborohydride affords the reduced derivative 33. Removal of the protecting group with a strong acid such as triflic or sulfuric acid affords the deprotected compound 34 which can then be coupled with a suitably substituted phenylboronic acid in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium acetate permits a coupling of the two aromatic species to yield 35. The reaction is normally carried out under biphasic conditions. That is, water is often employed along with an appropriate organic solvent, such as toluene or DMF.
The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo.
This invention includes pharmaceutical compositions and treatments which comprise administering to a mammal a pharmaceutically effective amount of one or more compounds as described above wherein G2 is Cxe2x95x90O as antagonists of the progesterone receptor. The invention further provides comparable methods and compositions which utilize one or more compounds herein wherein G2 is Cxe2x95x90S as agonists of the progesterone receptor. Moreover the invention further provides comparable methods and compositions which utilize one or more compounds herein wherein G1xe2x95x90O and G2xe2x95x90CR7CR8 are agonists of the progesterone receptor and when G1xe2x95x90CR7CR8 and G2xe2x95x90CR7CR8 are agonists of the progesterone receptor.
The progesterone receptor antagonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease. Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine mryometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors. Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock. When used in contraception the progesterone receptor antagonists of the current invention may be used either alone in a continuous administration of between 1 and 500 mg per day, or alternatively used in a different regimen which would entail 2-4 days of treatment with the progesterone receptor antagonist after 21 days of a progestin, in this regimen between 0.1 and 500 mg daily doses of the progestin (e.g. levonorgestrel, trimegestone, gestodene, norethistrone acetate, norgestimate or cyproterone acetate) would be followed by between 0.1 and 500 mg daily doses of the progesterone receptor antagonists of the current invention.
The progesterone receptor antagonists of this invention, used alone or in combination, can also be utilized in methods of treatment and/or prevention of benign and malignant neoplastic disease. Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors. Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock.
The progesterone receptor agonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake.
When used in contraception the progesterone receptor agonists of the current invention are preferably used in combination or sequentially with an estrogen agonist (e.g. ethinyl estradiol). The preferred dose of the progesterone receptor agonist is between 0.01 and 500 mg per day.
When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intrapenrtoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.